Didox potentiates the cytotoxic profile of doxorubicin and protects from its cardiotoxicity

Eur J Pharmacol. 2013 Oct 15;718(1-3):361-9. doi: 10.1016/j.ejphar.2013.08.009. Epub 2013 Sep 7.


The use of adjuvant therapies in cancer treatment is rationalized by potentiating the efficacy and/or protecting from the major side effects of chemotherapeutics. Didox, besides its antioxidant properties, is an inhibitor for DNA synthesis and repair which might recommend its use as adjuvant therapy. Herein, we have studied the effect of didox in potentiating the efficacy of doxorubicin (DOX) against liver cancer cells and protecting from its dose-limiting cardiotoxic effects. Didox combination with DOX significantly decreased in the IC50 of DOX to half its original value in Huh7 and HepG2 liver cancer cell lines. The calculated combination index (CI-value) indicated additive type of drug interaction (CI-value ranged from 0.81 to 0.9). Both didox and DOX significantly blocked the cell cycle in S-phase and their combination significantly increased cell cycle blockade. Also, didox combination significantly increase the caspase-3 level compared to DOX treatment alone. On the other hand, didox (150 mg/kg daily) significantly protected the cardiomyocyte membrane integrity and decreased the intra-cardiac oxidative stress induced by DOX treatment (15 mg/kg). This protective effect was reflected in reverting the cardiomegaly and cardio-pathological features induced by DOX treatment. Also didox prolonged the median survival time of mice treated with DOX and decreased the mortality risk by 3.7 folds. In conclusion, didox significantly potentiated the cytotoxicity of DOX in liver cancer cells and protected from its cardiotoxicity.

Keywords: Cardiotoxicity; Didox; Doxorubicin; Liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology*
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Doxorubicin / adverse effects*
  • Doxorubicin / pharmacology*
  • Drug Synergism
  • Heart / drug effects*
  • Hydroxamic Acids / pharmacology*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Poly(ADP-ribose) Polymerases / metabolism
  • Survival Rate


  • Cardiotonic Agents
  • Hydroxamic Acids
  • Doxorubicin
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • 3,4-dihydroxybenzohydroxamic acid